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Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis
  1. W H Bos1,2,
  2. G M Bartelds2,
  3. M Vis3,
  4. A R van der Horst4,
  5. G J Wolbink1,2,
  6. R J van de Stadt2,
  7. D van Schaardenburg2,3,
  8. B A C Dijkmans2,3,
  9. W F Lems3,
  10. M T Nurmohamed2,3,
  11. L Aarden1,
  12. D Hamann4
  1. 1
    Sanquin Research, Amsterdam, The Netherlands
  2. 2
    Jan van Breemen Institute, Amsterdam, The Netherlands
  3. 3
    VU University Medical Center, Department of Rheumatology, Amsterdam, The Netherlands
  4. 4
    Sanquin Diagnostic Services, Amsterdam, The Netherlands
  1. Dr W H Bos, Department of Immunopathology, Sanquin Research, PO Box 9190, 1006 AD Amsterdam, The Netherlands; w.bos{at}


Objective: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA).

Methods: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF-positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks.

Results: The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels.

Conclusion: ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint.

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  • Competing interests: None.

  • Funding: The JBI-Clinical Research Bureau with financial support of the Dutch Arthritis Association facilitated this study.

  • Ethics approval: The study was approved by the local medical ethics committee.

  • Patient consent: Obtained.

  • ▸ Additional figures are published online only at